Prosthetic mesh materials and the like have been used to reinforce the abdominal wall and to close abdominal wall defects. Polypropylene (PP) mesh is one of the most widely used and successful hernia mesh device. Polyester (POL) and porous teflon (PTFE) are also currently used. In many cases, including incisional and umbilical hernia repair and chest reconstruction, prosthetic mesh structures will come into direct contact with the abdominal viscera. Postoperative adhesions between the mesh and the intestine may occur, potentially leading to intestinal fistulization, and other problems.
The prior art contains several attempts to minimize postoperative adhesions associated with prosthetic mesh materials. Covering the prosthesis with peritoneum or other tissue to form a biological barrier between the implant and the bowel is one approach. Placement of a physical barrier between the surgical site and the surrounding tissue where adhesions are most commonly encountered is another.
The Ventrio Hernia. Patch (BARD Davol, Inc. Warwick, R.I.) is a multi-layer hernia repair device with a PTFE surface adjacent to the visceral abdominal cavity. PTFE is hydrophobic and resists adhesions.
U.S. Pat. No. 5,002,551 discloses a physical barrier formed of a knitted oxidized regenerated cellulose (Intercede(TC7)). The patent teaches that other physical barriers can include silicone elastomers and absorbable gelatin films. Based on studies in the literature, such physical barriers alone are not sufficient to reinforce the abdominal wall or to repair abdominal wall defects.
Jenkins et al., “A Comparison of Prosthetic Materials Used to Repair Abdominal Wall Defects”, Surgery, Vol. 94, No. 2, August 1983, pg. 392-398, describes a technique of placing an absorbable gelatin film (Gelfilm®) freely between a piece of Marlex® knitted polypropylene monofilament mesh and the abdominal viscera. The gelatin film dissolved after one week. Thereafter, the incidence of adhesions was reported to be the same as with using the Marlex mesh alone.
Several existing products address this problem:
Cousin Biotech Intramesh® T1, a two-sided polypropylene and ePTFE wall reconstruction prosthesis. Its two-sided structure has the advantage of one smooth side which reduces visceral adherence and a knitted side for better colonization of the peritoneum. One side in polypropylene monofilament knit, the other smooth anti-adhesive ePTFE.
Ethicon (Johnson&Johnson)—ULTRAPRO Partially Absorbable Lightweight Mesh. This was the first partially absorbable mesh available in the United States. They claim strong, secure repair with a flexible scar that lets abdominal wall move more naturally, as well as construction with trusted, proven materials.
Therapeutic options to treat excessive scarring are limited and most are not proven to be effective. Salinomycin is a novel small molecule that blocks myofibroblast (scar cell) formation. Salinomycin potently blocks the ability of the pro-scarring cytokine, transforming growth factor beta (TGFβ), to induce expression of alpha smooth muscle actin (αSMA), calponin and collagen, all of which are hallmarks of myofibroblasts.
Salinomycin also effectively blocks myofibroblast function (cellular contraction) without affecting viability. These novel studies highlight the potential of salinomycin to serve as the basis for new anti-scarring agents.
There is extensive work demonstrating the anti-scarring activity of salinomycin in vitro and in vivo. Cell culture studies show that low doses of salinomycin (50-200 nanomolar) block myofibroblast formation and function in human mesenchymal stem cells, human fibroblasts and fibroblasts from mouse, cat and pig.
Salinomycin can also be used effectively as a small molecule coating on silicone or temporary dressings such as PermeaDerm. Animal studies (i.e. mouse) show that silicone implants impregnated with low levels of salinomycin (1 micromolar coating solution) dramatically reduce peri-implant capsular scarring. In this study, silicone discs were impregnated with salinomycin or a control solvent and placed submuscular in mice. Surrounding tissue was harvested at 16 weeks and tissue sections were stained with Masson's trichrome. Salinomycin significantly reduced scar formation as evidenced by decreased capsule thickness.
In addition, Salinomycin is also an antimicrobial agent. Salinomycin and its derivatives exhibit high antimicrobial activity against Gram-positive bacteria, including the most problematic bacteria strains such as methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE), and Mycobacterium tuberculosis. Salinomycin is inactive against fungi such as Candida and Gram-negative bacteria. Gram-negative antimicrobials (vancomycin, ramplianin linezolid, meropenen, carbacephems, ceftriaxone or other) could be added to the biological coating of the 3D matrix or incorporated into the solid silicone membrane if desired using methods described here.
Additionally, we have shown that the low doses of salinomycin required for anti-scarring activity are non toxic, non-irritating and do not cause skin sensitization in a rabbit study that used salinomycin in cutaneous injection. Salinomycin was shown to be non-reactive in this model (no signs of erythema or edema) at 24, 48 and 72 hours after injection.